The present invention relates to a quinolinone derivative formulation having superior stability and bioabsorption, and its production method.
The present specification is based on a Japanese patent application filed in Japan (Japanese Patent Application No. Hei 10-62907), and the described contents of said Japanese patent application are incorporated as a portion of the present specification.
The inventors of the present invention reported in Japanese Unexamined Patent Application, First Publication No. Hei 9-255659 that a novel quinolinone derivative represented with chemical formula (I) has low toxicity, is effective against both immediate and delayed allergies, and is extremely useful as an antiallergic.
In addition, the inventors of the present invention also reported at the 12th Annual Convention of the Japan Pharmaceutical Society (Ohmiya, 1997) that the quinolinone derivative represented with chemical formula (I) demonstrates crystal polymorphism consisting of four crystal types of the xcex1, xcex2, xcex3 and xcex4 forms, and that each form exhibits different absorption in the body. However, the stability of these four crystal forms along with the preferable forms as pharmaceutical formulations were not clarified.
An object of the present invention is to provide a quinolinone derivative, having for its active ingredient the xcex2-form crystal and/or xcex3-form crystal of a quinolinone derivative represented with chemical formula (I) that is useful as a pharmaceutical, and particularly as an antiallergic, and having superior bioabsorption and stability, along with its production method.
As a result of eager research to achieve the above object, the inventors of the present invention found that, although each crystal form of the quinolinone derivative represented with chemical formula (I) is converted to an amorphous form resulting in improved bioabsorption as a result of crushing, the xcex2, xcex3 and xcex4 crystal forms demonstrate superior bioabsorption as compared with the xcex1 crystal form, and the xcex1, xcex2 and xcex3 crystal forms demonstrate superior stability as compared with the xcex4 crystal form. Thus, the inventors found that a pharmaceutical formulation having for its active ingredient the xcex2 crystal form and/or xcex3 crystal form demonstrates the most superior bioabsorption and stability. Moreover, the inventors found that a pharmaceutical formulation has even more superior stability by adding antioxidant and/or lubricant to a pharmaceutical formulation having for its active ingredient the xcex2 crystal form and/or xcex3 crystal form. Thereby, the inventors are led to completion of the present invention.
Namely, the present invention provides the following:
(1) quinolinone derivative formulation including for its active ingredient a xcex2 crystal form and/or a xcex3 crystal form of a quinolinone derivative represented with chemical formula (I): 
(2) a quinolinone derivative formulation including for its active ingredient a xcex2 crystal form and/or a xcex3 crystal form of a quinolinone derivative represented with chemical formula (I): 
xe2x80x83and including an antioxidant and/or a lubricant;
(3) a quinolinone derivative formulation according to (1) or (2), wherein the xcex2 crystal form and/or the xcex3 crystal form is obtained by recrystallizing from ethanol;
(4) a quinolinone derivative formulation according to any of (1) through (3), wherein a formulation form of the quinolinone formulation is selected from capsules, coated granules, coated tablets, or sugar-coated tablets, which can block lights;
(5) a production method of a quinolinone derivative formulation comprising: producing a formulation in a formulation form selected from capsules, coated granules, coated tablets, or sugar-coated tablets, which can block lights, by using a xcex2 crystal form and/or a xcex3 crystal form of the quinolinone derivative represented with chemical formula 
(6) a production method of a quinolinone derivative formulation comprising: producing a formulation in a formulation form selected from capsules, coated granules, coated tablets or sugar-coated tablets, which can block lights, by using a xcex2 crystal form and/or a xcex3 crystal form of the quinolinone derivative represented with chemical formula 
xe2x80x83and an antioxidant and/or a lubricant; and
(7) a production method of a quinolinone derivative formulation according to (5) or
(6), wherein the xcex2 crystal form and/or xcex3 crystal form is obtained by recrystallizing from ethanol.